Uterine anomalies and pregnancy outcome following resectoscope metroplasty.

OBJECTIVE: To compare reproductive outcome in women with uterine anomalies and women with a normal uterus, and evaluate the effect of resectoscope metroplasty. METHODS: The pregnancy outcomes, past and present, of 105 women with congenital uterine anomalies were compared with those of 182 women with a normally shaped uterus. The outcomes of 25 women with septate and bicornuate uteri before and after resectoscope metroplasty were also analyzed. The chi(2) and Mann-Whitney U test were used for statistical analysis, with P<0.05 considered statistically significant. RESULTS: Uterine anomalies were associated with higher rates of spontaneous abortion, preterm delivery, intrauterine growth retardation, breech presentation, and cesarean delivery (P<0.001). The highest incidence of early spontaneous abortion was noted among women with septate uteri, and the highest incidence of preterm labor was noted among women with arcuate or bicornuate uteri. Among women with arcuate uteri, significantly lower gestational age and birth-weight were observed compared with any other type of adverse outcome. Compared with their previous pregnancies, the abortion rates were lower and delivery rates were higher in women who conceived following hysteroscopic metroplasty (P<0.001). CONCLUSION: Resesctoscope metroplasty significantly improved pregnancy outcome in women with uterine anomalies.

A significance of immunohistochemical determination of steroid receptors, cell proliferation factor Ki-67 and protein p53 in endometrial carcinoma.

OBJECTIVES: The aim of the study was to preoperatively predict the biologic behavior of the endometrial carcinoma using immunohistochemical analysis of the p53 protein and Ki-67 expression, and estrogen receptor (ER) and progesterone receptor (PR) status, in the material obtained by fractional curettage. METHODS: One hundred and thirty-six patients with primary endometrial carcinoma were included in the study. In all 136 patients, the fractional curettage was performed before the hysterectomy, and the diagnosis of endometrial carcinoma was confirmed pathohistologically after the surgical procedure on the hysterectomy specimens. The significance of the prognostic factors was assessed using univariate and multivariate analyses. The cutoff values of the percentage of ER, PR, p53, and Ki-67 positive cells in terms of survival probability determination were obtained as the values of the highest chi-square test, using proportional-risk regression method. A multivariate Cox regression analysis was performed to estimate the influence of several clinical, pathohistologic, and immunohistochemical covariates to patients' survival. Survival curves were determined by the Kaplan-Meier product-limit method based on the most recent clinical status. RESULTS: According to the histologic type of the tumor, fractional curettage specimens revealed 111 histologically favorable types (81.6%) and 25 unfavorable types (18.4%). The data indicate that ER, PR, Ki-67, and p53 levels of the hysterectomy specimens and those of the preoperative specimens were in fairly good agreement. The patients with the most favorable tumor grade (G I) had significantly better prognosis when the percentage of p53 positive cells was less than 15%. In the group of patients with histologic grade II, the survival was affected by ER expression (more than 30% of positive cells) and p53 levels (less than 15% of positive cells). None of the parameters was predictive in the group of patients with histologic grade III. CONCLUSIONS: We found that determination of immunohistochemical parameters (ER, PR, and p53) on well-differentiated and moderately differentiated endometrial carcinoma of favorable histologic type obtained by curettage enables the recognition of the patients with favorable prognosis, who should not be treated by radical surgery.

Hospitalization vs. outpatient care in the management of triplet gestations.

OBJECTIVE: To compare the course and outcome of triplet gestations under a preventive care strategy that includes hospitalization, surveillance, bed rest, and daily specialized care from the beginning of the second trimester, with pregnancies managed according to the Croatian standard outpatient care protocol for multiplets. METHODS: A retrospective study of 79 triplet pregnancies. Preventive hospitalization from the beginning of the second trimester, with complete bed rest and all necessary interventions, was chosen by 55 women (Group I). The remaining 24 women (Group II) elected the standard outpatient protocol for multiple pregnancies. Outpatient management with prophylactic bed rest was initiated at home as soon as the multiple pregnancy was diagnosed. After 28 weeks of gestation, all outpatients were hospitalized until delivery irrespective of symptoms. RESULTS: There was no difference between the groups regarding maternal age, race, pre-pregnancy weight and height, weight gain during the first 24 weeks of pregnancy, or the proportion of pregnancies achieved with assisted reproductive technology. Four out of 55 women (7.2%) from Group I and 4 out of 24 women (12.5%) from Group II had monochorionic triplet pregnancies (P=n.s.). Nulliparity was more frequent in Group I than in Group II (P=0.006). Elective cesarean delivery was significantly more frequent in Group I (46 out of 55 gestations, 72.7%) than in Group II (9 out of 24 gestations, 37.5%), P=0.024. Gestational age at delivery and mean birth weight were significantly higher in Group I than in Group II (P<0.001). Deliveries up to 28 weeks of pregnancy were infrequent in Group I (P=0.02). Thirty-three gestations in Group I (60%) and 6 (25%) in Group II had a duration of 33-36 weeks (P<0.001). Two out of 55 triplet gestations in Group I (3.6%) and 4 out of 24 in Group II (16.7%) ended in spontaneous abortion (P=0.053). The survival of the three triplets was more frequent in Group I than in Group II (P=0.048). For gestations reaching 24 weeks or more, the fetal and perinatal death rate was significantly lower in Group I (P<0.001). In Group I the intrauterine death rate for fetuses weighing 1500 g or less was also significantly lower (P=0.007), and the early neonatal death rate was almost half (15.8 vs. 28.9%, P=0.157). There were no differences in other pregnancy complications between the two groups except significantly more frequent preterm premature rupture of membranes and preterm labor requiring parenteral tocolysis in Group II (P=0.042 and 0.036, respectively), and significantly more frequent fetal growth retardation in Group I (P<0.001). CONCLUSION: Preventive hospitalization offers a better outcome for triplets even though prolonged hospitalization and all other procedures necessary to achieve optimal pregnancy outcome are also offered in the Croatian standard outpatient care protocol for multiplet pregnancies.

Glutathione and glutathione S-transferases as early markers for ovarian carcinomas: case series.

AIM: To determine the activity of glutathione (GSH) and concentrations of glutathione S-transferases (GST), urokinase type plasminogen activator (uPA), and plasminogen activator inhibitor type 1 (PAI-1), and to evaluate their diagnostic and prognostic value and possible correlation with clinical and histopathological prognostic factors for ovarian carcinomas. METHODS: The concentrations of GSH, uPA, PAI-1, and activity of GST were analyzed in 35 tissue samples taken from 10 normal ovaries, 10 benign, 10 primary malignant, and 5 metastatic ovarian tumors. The GSH level and GST activity were determined by spectrophotometric methods, and uPA and PAI-1 concentrations by ELISA commercial kits. RESULTS: GSH concentrations were significantly higher in primary malignant (126.3+/-12.8 nmol/mg protein) and metastatic (160.5+/-24.3 nmol/mg protein) ovarian tumor specimens than in normal ovarian tissue (48.9+/-8.1 nmol/mg protein, p<0.003 for both carcinoma groups) or benign ovarian tumor samples (35.2+/-5.0 nmol/mg protein, p=0.001). The GST activity was significantly higher in primary malignant (245.8+/-22.7 nmol/min/mg protein) and metastatic (303.7+/-48.8 nmol/min/mg protein) ovarian tumor tissues than in benign tumor specimens (105.9+/-16.2 nmol/min/mg protein, p<0.004 for both carcinoma groups) or normal ovarian tissue samples (133.2+/-32.0 nmol/min/mg protein, p<0.044 for both carcinoma groups). There were no statistical differences in uPA and PAI-1 concentrations between normal, benign, and malignant tumor samples. Concentrations of GSH, uPA and PAI-1, and activity of GST were independent from histopathological and clinical prognostic factors. CONCLUSION: Increased GSH concentration and GST activity found in primary malignant and metastatic ovarian tumor samples were independent of histopathological and clinical prognostic factors, suggesting that they could be early markers for ovarian carcinomas.

Antenatal predictors of the neurologic sequelae at 3 years of age: a multivariate analysis.

OBJECTIVE: To study the association between fetal blood flow abnormalities and the occurrence of long-term neurologic sequelae. STUDY DESIGN: Umbilical, aortic and middle cerebral artery blood flow parameters were obtained by Doppler examination and retrospectively analyzed in 128 high-risk singleton pregnancies, followed by neurologic examination of the surviving children at 3 years of age. Traditional parameters of neurologic outcome (Apgar scores, intrauterine growth retardation (IUGR), umbilical artery pH and base deficit, gestational age, birth weight, newborn encephalopathy, mode of delivery, fetal heart rate, neurosonographic examination) were included as possible confounding factors. Mann-Whitney U-test, Student's t-test, analysis of variance or Fisher's exact test, where applicable, were used for the univariate analysis. A stepwise logistic regression procedure was conducted to test the independent association of selected perinatal risk factors on neurological outcome. Statistical significance was assumed at P<0.05. RESULTS: Eighteen out of 114 surviving children suffered neurologic illness at 3 years of age. Four children had major neurologic dysfunction and the remaining 14 suffered minor or mild form of the disease. Although blood flow parameters and various perinatal parameters did not differ significantly between the group of children with major neurologic dysfunction and healthy children, aortic resistance index showed an independent association with occurrence of minor or mild neurologic disabilities. CONCLUSION: Antenatal evaluation of the aortic blood flow might be an important predictive variable for permanent neurologic disturbances.

Intravesically administered ketoprofen in treatment of detrusor instability: cross-over study.

AIM: To evaluate the therapeutic efficacy of intravesically administered ketoprofen in patients with urodynamically verified detrusor instability. METHODS: This double-blind randomized placebo-controlled cross-over study included 30 patients with urodynamically verified detrusor instability. Their mean age was 44+/-3.6 years (range 37-49) and the median of the parity was 2 years (1-3). The mean duration of symptoms was 18.3+/-3.1 months (range 14-23). After a 6-week screening, patients were randomized to receive ketoprofen or placebo once a day for 4 weeks. Out of 30 patients, 16 started with ketoprofen, and 14 received placebo. After a week of washing period, 16 patients received placebo, and 14 received ketoprofen. The solution for intravesical application was 50 mL of saline with 2 mL (100 mg) of ketoprofen warmed to 37 degrees C. The placebo solution contained 2 mL of distilled water instead of ketoprofen. The assessment including micturition diaries, cystometric measurements, and bacteriological analysis of urine specimens was performed at the beginning of the study and after the treatment. RESULTS: The subjective cure rate was 18/30 after ketoprofen. The instability index was lower after ketoprofen than before treatment or after placebo (p<0.001). Maximal cystometric capacity and the urinary bladder volume at which the patients felt urgency to void were larger after ketoprofen than before it (p<0.001) or after placebo (p<0.001). The number of patients with uninhibited bladder contractions decreased significantly after ketoprofen, but not after placebo (p<0.001). No side effects were observed. CONCLUSION: Intravesically administrated ketoprofen is a feasible and effective treatment for detrusor instability.

Pregnancy outcome in renal transplant recipients.

OBJECTIVE: To correlate pregnancy outcome with complications in pregnancy and transplantation-to-pregnancy interval in renal transplant recipients in Croatia. METHOD: Data on 23 pregnancies after prepregnancy stabilization of blood pressure and normalization of graft function were retrospectively analyzed. RESULT: The mean interval between transplantation and conception was 3.1 years. Primary renal disease was chronic glomerulonephritis in 7, chronic pyelonephritis in 7 and agenesis of right kidney and stenosis of left renal artery in 1 patient. There were 10 term and 5 preterm deliveries, 6 induced and 2 spontaneous abortions. The mean gestational age was 38.1 weeks and the mean newborn birthweight was 3015 g. The prematurity rate was 21.7%. Patients with arterial hypertension in pregnancy, elevated serum creatinine level and bacteriuria, as well as those with conception occurring less than 2 years after transplantation, had a higher rate of therapeutic and spontaneous abortions, preterm deliveries and low birth weight infants. CONCLUSION: The interval between transplantation and conception, as well as allograft function during pregnancy, seem to be of great importance for successful obstetric outcome in renal transplant patients.

Pheochromocytoma with negative urinalysis in pregnancy.

We present a rare case of adrenal pheochromocytoma in pregnancy, with serial 24-h urine specimen collections showing normal concentrations of catecholamine metabolites. The diagnosis was based on clinical presentation, abdominal ultrasound, and magnetic resonance imaging, and was confirmed on post-operative pathohistological examination. Clinical suspicion of pheochromocytoma in pregnancy should be sufficient to implement adequate therapeutic measures, regardless of urine catecholamine concentrations.

Maternal neonatal outcome in quadruplet and quintuplet versus triplet gestations.

OBJECTIVE: Examination and comparison of the natural histories of triplet versus quadruplet and quintuplet gestations. STUDY DESIGN: A retrospective study of sixty-four multifetal pregnancies (fifty-two sets of triplets, nine sets of quadruplets and three sets of quintuplets) cared for during past 12 years in our department. Quintuplets and quadruplets were compared with triplet pregnancies according to gestational age, birthweight, pregnancy complications and perinatal outcome. Student's t-test, Fisher exact test and chi2 test were used for statistical analysis, considering P value of <0.05 as statistically significant. RESULTS: Although mean gestational age at delivery between triplets and higher order gestations was not significantly different, birthweight of quadruplets and quintuplets was significantly lower. Pregnancy complications, including intrauterine growth retardation, were equally distributed between the groups. Early neonatal and perinatal mortality were significantly higher in quadruplets and quintuplets than in triplets. Surprisingly, survival of growth retarded fetuses was better than survival of their eutrophic counterparts. The spontaneous loss rate was 11.5% for entire triplet gestation and 16.7% for quadru- and quintuplet pregnancies. CONCLUSIONS: As the spontaneous loss rate of triplets and higher order pregnancies observed in our study is quite similar to pregnancy loss rate caused by multifetal pregnancy reduction, conservative management of multifetal pregnancies in specialised tertiary centers seems to be a prudent solution.

The influence of dexamethasone treatment of pregnant rats on the development of chromaffin tissue in their offspring during the fetal and neonatal period.

The aim of these examinations was to determine the influence of dexamethasone (Dx)-treatment of gravid females, on day 16 of gestation on the development of medullary chromaffin tissue of their fetuses and neonatal offspring. In conducting these investigations we used stereological as well as spectrofluorimetric measurements, in 20-day-old fetuses and 1-, 3-, 5-, 7-, 9-, 11-, 13- and 14-day-old neonatal rats. Single Dx-treatment (1.5 mg/kg bw) of the dams led to a significant decrease in body and adrenal weight of their fetuses and neonatal offspring, and also reduction of the medullary volume and the number of chromaffin cells during the entire period examined as a result of decreased cell proliferation in the fetal and early neonatal period (till the 5th day of age). The proliferative activity of the chromaffin cells was evaluated through the mitotic index after applying the cytostatic vincristine-sulphate. During the second neonatal week the mitotic index showed significantly higher values in comparison with the corresponding controls, which indicates that there is regeneration and recovery of the adrenal gland medulla. Adrenaline content in the adrenal gland tissue of offspring of Dx-treated dams was significantly reduced only on the 1st neonatal day. Thus, the change in blood glucocorticoid level of pregnant females after a single Dx injection during the period critical for development of the hypothalamo-pituitary-adrenal system in fetuses affects the development and kinetics of medullar chromaffin cell division.

Treatment of pregnant females with dexamethasone influences postnatal development of the adrenal medulla.

In the light of the mutual dependence between the adrenal cortex and medulla, the aim of this work was to examine whether glucocorticoid treatment of pregnant rats affects the development of the adrenal medulla of their offspring in the postnatal period. Pregnant rats were treated with dexamethasone (Dx) in a daily dose of 0.3 mg Dx/kg b.w. during days 16-20 of gestation. The structure and function of the adrenal medulla of their 14-day-old offspring were estimated on the basis of the morphometric parameters of the gland, chromaffin cell mitotic index and adrenal gland adrenaline content. Stereological analysis was carried out at the light microscopic level, the mitotic index was determined by counting the number of metaphase arrested chromaffin cells following the administration of vincristine-sulphate, whereas adrenaline content in the adrenal gland was measured fluorimetrically. Plasma ACTH concentrations of the offspring were also determined by RIA. Long term Dx treatment of pregnant rats caused a significant decrease of the total volume of adrenal chromaffin tissue in the 14-day-old offspring as well as a reduction in the number of chromaffin cells and the average cell and nuclear volumes. The proliferative activity of the chromaffin cells was also lower than in the control offspring. These changes were accompanied by a significantly reduced adrenaline content in the adrenals. The results of this work show that glucocorticoid excess during the period of pregnancy when the fetal adrenal medulla is formed has a strong inhibitory effect on the adrenal medulla of the offspring at the age of 14 days.

The influence of prolonged dexamethasone treatment of pregnant rats on the perinatal development of the adrenal gland of their offspring.

The effects of prolonged dexamethasone (Dx) administration to pregnant rats on the structure and function of the adrenal glands of fetal and neonatal offspring have been investigated by combined stereological and ultrastructural methods, as well as by metaphase index determination. Pregnant rats were injected subcutaneously with Dx (0.3 mg/kg body weight/day) during 5 days, starting from day 16 of gestation. The dams and their fetuses were killed 24 hr after the last injection. The neonatal offspring were killed in the same way on the 3rd and 14th day of life. Because in fetal and 3-day-old neonatal rats zona reticularis (ZR) was poorly defined and could not be clearly seen as a separate zone, zona fasciculata (ZF) and ZR were analyzed as one, inner zone (IZ). In 14-day-old rats ZF and ZR were analyzed separately. Proliferative activity of adrenocortical cells was estimated following the application of Vincristine sulphate. Dx treatment of pregnant rats induced a marked decrease of fetal adrenal gland volume and the volumes of zona glomerulosa + capsula (ZG + C) and IZ as the consequence of atrophic changes in the gland and reduction of the average volume and total number of adrenocortical cells. Similar morphometric changes were found in 3- and 14-day-old pups. However, in 3-day-old animals the number of cortical cells in the ZG was increased, whereas on the 14th postnatal day cortical cell number remained decreased only in the ZF. The multinuclear giant cells, numerous lymphocytes, and the resorption zones, present in the adrenal cortex of fetuses and 3-day-old pups of both experimental and control dams, were not seen in 14-day-old offspring. These results demonstrate that prolonged treatment of pregnant rats with Dx in the period when intensive differentiation of the fetal hypothalamo-hypophyseal system takes place inhibits proliferative activity of adrenocortical cells and evokes considerable atrophic changes in the adrenal glands of offspring from 20 days gestation to 14 days after birth. The histological appearance of the adrenal cortex and the ultrastructure of adrenocortical cells suggest that cortical cell function was inhibited.

The effect of dexamethasone on the adrenal gland in fetal and neonatal rats.

The development and regeneration of the adrenal glands were examined by stereological and morphological methods in 20-day-old fetal, as well as 3-day- and 14-day-old neonatal male rats born to dams treated with dexamethasone (Dx) on day 16 of gestation. In the fetuses and 3-day-old rats, zona fasciculata (ZF) and zona reticularis (ZR) were analyzed as one inner zone (IZ), while in 14-day-old animals they were analyzed separately. Single Dx treatment (1.5 mg/kg b.w.) of the dams led to atrophic changes in the adrenal cortex of the fetuses. These changes were visible to a certain degree up to the 14th neonatal day. Administration of Dx to pregnant rats induced a significant decrease of both adrenal weight and volume, as well as the volume of zona glomerulosa + capsule (ZG + C) and IZ, both in fetuses and 3-day-old rats. This was due to a decrease in the number but not the volume of cortical cells. Also, necrotic cortical cells, infiltrations and resorption zones accompanied by the presence of macrophages, giant cells and lymphocytes were observed. In 14-day-old animals, the degree of atrophic changes in the adrenal cortex was reduced. Changes were observed only in ZR which was decreased in volume resulting from both a significant decrease of the volume and number of cortical cells. Then number of macrophages was somewhat increased, while giant cells were not present. However, the total number of parenchyma cells in ZG was increased, pointing to the possibility of renewal of cortical cells within this zone. The results of the present study demonstrate that even a single Dx dose given to pregnant rat during the period critical for the development of the hypothalamo-pituitary-adrenal system in the fetuses leads to marked changes in the structure and function of the fetal adrenal glands which are partially maintained up to the 14th day of postnatal life.